Throughout the history of human medicine, various compounds have been used for the relief of pain. In particular, a class of compounds of plant origin known as opiates has been used since prehistoric periods for analgesic and euphoric purposes. Even today the opiate drug morphine is used as an analgesic for significant pain, and morphine is still an important benchmark for clinical studies: Morphine is the most widely prescribed injectable opioid today, despite its narcotic side effects. The opioid derivative hydrocodone is the most commonly prescribed drug in the United States. Acute opioid toxicity from overdose can result in respiratory depression and death, whereas chronic use can lead to physical dependence, addiction, and severe opioid-induced bowel dysfunction.
Despite significant side effects, opioids are the first choice for the treatment of moderate to severe pain (including inflammatory), both acute and chronic. Current analgesics, including morphine, fentanyl, oxycodone and hydrocodone act primarily at mu-opioid receptors (MOR). Activation of this receptor subtype is responsible for many of the side effects associated with these drugs, such as respiratory depression, constipation, addiction, dependence, and immunosuppression. These side effects limit the use of morphine and other opioids to treat both acute and chronic pain.
Currently available opioid drugs are the primary choice for the treatment of moderate to severe pain and account for over 180 million prescriptions annually in the United States. Representative opioid drugs in this list include hydrocodone, oxycodone, oxymorphone, codeine, methadone and morphine.
The majority of clinically available opioids act almost exclusively at the MOR. Agonism of the MOR mediates not only the analgesic actions of this class of drugs, but also many of the side effects of opioids including respiratory depression, constipation, addiction liability, tolerance/physical dependence and immunosuppression. These side effects significantly limit the usefulness of opioid analgesics, especially in cases of non-malignant chronic pain. An additional constraint in the reliance upon MOR selective analgesics is their limited efficacy in certain inflammatory and neuropathic pain states, requiring dose escalations that further increase compound side effects. These shortcomings drive the sustained efforts to develop novel analgesics that have equivalent or better efficacy compared to conventional opioids for a variety of pain states, while limiting the side effect potential.
Endogenous opioid peptides synthesized by vertebrates in general, and mammals in particular, bind to the same receptors as the exogenous opioid molecules including morphine. The endogenous peptides are known by the generic terms endorphins, and endorphins have been subject of much discussion and research since their discovery in the 1970s. These endogenous opioids are believed to be the natural source of various euphoric experiences reported by people, including the “runner's high” and the feelings experienced by some after eating chocolate. Although the evidence about these experiences is to a large degree subjective, there is no question that endogenous opioid peptides play a critical role in the various sensory emotional motivational and cognitive functions.
A related class of endogenous opioids has been isolated from amphibian skin extracts and are known as the deltorphins. Deltorphins are small peptides that display high specificity. There are both natural and synthetic deltorphins. Deltorphins are well known to actively engage the opioid receptors and can produce strong analgesic effects when delivered to the brain or spinal cord. However, the use of endorphins in general, and deltorphins in particular, has not moved from the theoretical to the therapeutic reality, in large part based on difficulties in their administration and stability, and an inability to deliver the molecules across the blood brain barrier.
Delta Opioid Receptors (DOR) were first described in 1977 (Lord et al., 1977) and subsequently, several classes of peptide and non-peptide based molecules have been synthesized that selectively stimulate this receptor. Selective DOR molecules include the modified enkephalin analog, DPDPE (Mosberg et al., 1983), deltorphin-based peptides (Kreil et al., 1989) and analogs of BW373U86 (e.g., SNC80; Bilsky et al., 1994; Calderon et al., 1994; 2004). Preclinical efficacy studies of these compounds, along with DOR-selective antagonists, provide a convincing rationale for pursuing DOR agonists as analgesic agents. In addition, DOR knockout mice exhibit increased pain behaviors following an inflammatory or neuropathic-based insult (Gavériaux-Ruff et al., 2008; Nadal et al., 2006). Interestingly, upregulation and altered trafficking of DOR occurs following induction of various pain states in rodents (Cahill et al., 2003; 2007; Walwyn et al., 2005). DOR selective compounds also have significantly reduced the tumor burden in multiple animal models.
There is a critical need for improved opioids with high efficacy, but without the severe side effects associated with currently available therapies. Accordingly, the present invention addresses this need by using novel synthetic chemistry to generate novel compounds that have improved pharmacological properties for targeting DOR.